PHA/NHLBI K08/K23 Award Winner 2007

Peter Oishi, M.D.

University of California San Francisco “Vascular Dysfunction with Increased Pulmonary Blood Flow: A Role for PPAR Gamma”NHLBI Mentored Clinical Scientist Development Award (K08) July 1, 2007 – June 30, 2012

Summary of Research Project:

Vascular Dysfunction with Increased Pulmonary Blood Flow: A Role for PPAR Gamma

Congenital heart defects, which are birth defects that result in anatomic abnormalities of the heart, afflict as many as 1% of all born infants. Although there are many different types of defects, several common defects disrupt the normal separation between the blood that flows from the heart to the lungs and the blood that flows from the heart to the body. As a result, these defects cause an abnormally increased amount of blood to flow through the lungs. Over time, this increased blood flow to the lungs causes injury to the blood vessels of the lung. Normally, the blood vessels of the lung are maintained in a relaxed dilated state, and thus allow blood to flow easily under low pressure. However, after exposure to abnormally increased blood flow, the blood vessels of the lung begin to loose this relaxed state, and become prone to periods of intense constriction. This can diminish the amount of oxygen delivered to the body from the lungs, and can place a significant strain on the heart which must pump blood through the lungs against an abnormally increased pressure. Even worse, if the disease process continues, the blood vessels of the lung begin to change by thickening and decreasing their internal size. This can permanently increase the resistance of blood flow through the lung and increase the pressure within the lung’s vessels. This increased pressure is called hypertension, and since it develops within the lung, it is called pulmonary hypertension.

My research is focused on understanding the basic mechanisms that link increased blood flow through the lungs with the development of this pulmonary hypertension. Only by understanding these processes, can novel treatment strategies be developed to help patients with this disease. In order to study basic biochemical, cellular, and molecular mechanisms that control the development of pulmonary hypertension, lung tissue and lung blood vessels must be examined. This presents a significant problem for researchers, since obtaining lung tissue from patients would require very invasive and potentially dangerous surgery. Therefore, our laboratory group has developed a large animal model that closely mimics the human disease. With this model the controlling mechanisms can be explored.

We have previously demonstrated alterations in important factors produced by lung vessels, such as nitric oxide and endothelin-1, that contribute to the development of pulmonary hypertension in the setting of congenital heart defects. In fact, therapies that increase nitric oxide signaling (sildenafil) and that block endothelin-1 (bosentan) are currently used to treat patients with pulmonary hypertension.

More recently, our work has explored the role of reactive oxygen species, which are molecules derived from oxygen that contribute to the development of a number of vascular diseases, including hypertension, diabetes, and stroke, in the development of pulmonary hypertension. Furthermore, preliminary studies in our laboratory have identified a potential role for a recently discovered class of receptors in the body termed peroxisome proliferator-activated receptors, or PPAR. This line of research is exciting because drugs that activate these receptors are currently available commercially for the treatment of diabetes.

Curriculum Vitae

Position: Assistant Professor Department of Pediatrics, Division of Critical Care University of California San Francisco

2005 Platform Presentation, “Increased Pulmonary Blood Flow is Associated with an Increase in NOS Activity and Gene Expression But a Decrease in Bioavailable NO in an Animal Model of Congenital Heart Disease – A role for superoxide production?” Pediatric Academic Societies’ Meeting, Washington, D.C.

Title: Vascular Dysfunction with Increased Pulmonary Blood Flow: A role for PPAR Gamma Principle Investigator: Peter Oishi Agency: National Heart Lung and Blood Institute, K08 1/01/07 to 12/31/10 The objective of this project is to elucidate the role of PPAR gamma in the pulmonary vascular dysfunction that develops secondary to congenital cardiac defects with increased pulmonary blood flow.

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